دورية أكاديمية
Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis.
| العنوان: | Repositioning of ezetimibe for the treatment of idiopathic pulmonary fibrosis. |
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| المؤلفون: | Lee C; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; These authors contributed equally to this work., Kwak SH; Division of Pulmonology, Allergy and Critical Care Medicine, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea.; These authors contributed equally to this work., Han J; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.; Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea., Shin JH; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea., Yoo B; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea., Lee YS; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.; Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea., Park JS; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea., Lim BJ; Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea., Lee JG; Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim YS; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea., Kim SY; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.; These authors contributed equally to this work., Bae SH; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea soohanbae@yuhs.ac.; Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea.; These authors contributed equally to this work. |
| المصدر: | The European respiratory journal [Eur Respir J] 2024 May 16; Vol. 63 (5). Date of Electronic Publication: 2024 May 16 (Print Publication: 2024). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: European Respiratory Society Country of Publication: England NLM ID: 8803460 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1399-3003 (Electronic) Linking ISSN: 09031936 NLM ISO Abbreviation: Eur Respir J Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Sheffield, United Kingdom : European Respiratory Society Original Publication: Copenhagen : Published jointly by the Society and Munksgaard, 1988- |
| مواضيع طبية MeSH: | Ezetimibe*/therapeutic use , Ezetimibe*/pharmacology , Idiopathic Pulmonary Fibrosis*/drug therapy , Autophagy*/drug effects , Drug Repositioning* , Disease Models, Animal* , Anticholesteremic Agents*/therapeutic use , Anticholesteremic Agents*/pharmacology, Animals ; Humans ; Mice ; Male ; Female ; Mice, Transgenic ; Bleomycin ; Lung/pathology ; Lung/drug effects ; Fibroblasts/metabolism ; Fibroblasts/drug effects ; Retrospective Studies ; Aged ; Middle Aged ; Mice, Inbred C57BL ; Myofibroblasts/drug effects ; Myofibroblasts/metabolism ; Cholesterol/metabolism |
| مستخلص: | Background: We previously identified ezetimibe, an inhibitor of Niemann-Pick C1-like intracellular cholesterol transporter 1 and European Medicines Agency-approved lipid-lowering agent, as a potent autophagy activator. However, its efficacy against pulmonary fibrosis has not yet been evaluated. This study aimed to determine whether ezetimibe has therapeutic potential against idiopathic pulmonary fibrosis. Methods: Primary lung fibroblasts isolated from both humans and mice were employed for mechanistic in vitro experiments. mRNA sequencing of human lung fibroblasts and gene set enrichment analysis were performed to explore the therapeutic mechanism of ezetimibe. A bleomycin-induced pulmonary fibrosis mouse model was used to examine in vivo efficacy of the drug. Tandem fluorescent-tagged microtubule-associated protein 1 light chain 3 transgenic mice were used to measure autophagic flux. Finally, the medical records of patients with idiopathic pulmonary fibrosis from three different hospitals were reviewed retrospectively, and analyses on survival and lung function were conducted to determine the benefits of ezetimibe. Results: Ezetimibe inhibited myofibroblast differentiation by restoring the mechanistic target of rapamycin complex 1-autophagy axis with fine control of intracellular cholesterol distribution. Serum response factor, a potential autophagic substrate, was identified as a primary downstream effector in this process. Similarly, ezetimibe ameliorated bleomycin-induced pulmonary fibrosis in mice by inhibiting mechanistic target of rapamycin complex 1 activity and increasing autophagic flux, as observed in mouse lung samples. Patients with idiopathic pulmonary fibrosis who regularly used ezetimibe showed decreased rates of all-cause mortality and lung function decline. Conclusion: Our study presents ezetimibe as a potential novel therapeutic for idiopathic pulmonary fibrosis. Competing Interests: Conflict of interest: The authors have applied for a patent entitled “Pharmaceutical composition for preventing, improving, alleviating or treating pulmonary fibrosis containing ezetimibe as an active ingredient”. The authors have nothing else to disclose. (Copyright ©The authors 2024.) |
| التعليقات: | Comment in: Eur Respir J. 2024 May 16;63(5):. (PMID: 38754951) |
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| تواريخ الأحداث: | Date Created: 20240215 Date Completed: 20240516 Latest Revision: 20240518 |
| رمز التحديث: | 20240518 |
| مُعرف محوري في PubMed: | PMC11096666 |
| DOI: | 10.1183/13993003.00580-2023 |
| PMID: | 38359963 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1399-3003 |
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| DOI: | 10.1183/13993003.00580-2023 |